ABSTRACT Dendritic cells (DCs) are key immune sentinels that link innate immune recognition to adaptive immunity, and therefore shape the magnitude and type of T cell responses. The DC lineage includes type I interferon-producing plasmacytoid DCs (pDCs) and two major subsets of antigen-presenting classical DCs (cDCs). Human studies are typically restricted to in vitro-derived DCs or to DCs from peripheral blood or a single tissue. In contrast, the composition and functionality of DC populations in tissues and lymphoid organs has never been interrogated within the entire human body. Cytomegalovirus (CMV) is widely distributed in the normal human population in latent form, whereas active CMV in immunodeficient subjects causes significant morbidity and mortality. The population dynamics and function of human DCs in lanetnt and active CMV infections remain poorly understood. The goal of this project is to elucidate the function of human DCs in antiviral immunity on the whole-body scale, focusing on CMV infection. We will utilize several unique human immunology resources, including tissues from recently deceased organ donors and blood samples from transplantation recipients. We will combine these resources with cutting- edge genomics and functional analysis to pursue three Specific Aims. In Aim 1, we will characterize the subset composition, phenotype and transcriptional signatures of DCs from multiple tissues of organ donors. In Aim 2, we will study the response of primary human DC subsets to primary CMV-infected cells, and perform comprehensive transcriptomic analysis of CMV-induced DC activation. In Aim 3, we will correlate the composition and function of tissue DCs with the presence of latent CMV infection and with CMV-specific T cell responses. In addition, the phenotype and function of DCs will be analyzed in the blood of transplantation recipients with or without the active CMV infection. Collectively, these studies would provide the first comprehensive analysis of human DC lineage and subsets on the scale of the entire body; generate a wealth of reference data on DC composition and activity; and provide insight into the role of DCs in the latent and active CMV infection.